Bis amino ethyl disulphide compounds



BIS AMINO DISULPHIDE COMPOUNDS Maurice Joullie,: Saint-Germain-en-Laye, and Michel Lani-re, Gabriel Maillard, and Pierre Muller, ,Paris, France, assignors to Recherches et Propaganda Scien- Patented July 5, 1960 l and X is an-atom of analkali metal, with a compoundoi where Y is a halogen atom.

, Preferably in the foregoing process X is sodium or potassium, Y is chlorine, and the reactants are present tifiques (Socit a Responsabilit Limite), Paris,

According to the present invention there are provided compounds of the general Formula I:

R 0 0 c i o 0 0 R;

N-c*cHr-sS-CH:CN Rz V Ra R 0 0 c 0 0 Br where R is a lower alkyl group and R is a hydrogen atom or an acyl group while R is a hydrogen, or R and R together with the N to which they are attached repre sent a phthalamido group. The said compounds are the bis-(,B-amino-;3,,8-dicarbalkoxy ethyl)disulphides and his- (fl-acylamido-fifi-diearbalkoxyethyl)disulphides or bis- (fl-phthalimido-fi,fl-dicarbalkoxycthyl) disulphides. The

said compounds are valuable intermediates for use inthe synthesis of cystine to which they may be converted by hydrolysis and decarboxylation as described and claimed in our copendingi patent application Serial No.

624,733, filed November 28, 1956. The process described and claimed in our patent application Serial No;

624,733 for the synthesis of cystine comprises the step of subjecting a bis-(,8-amino-p e-dicarbalkoxyethyl) disulphide, a bis-(13-acylamido-fl,fi-dicarbalkoxyethyl) disulphide or a bis-(fl-phthalimidoflfi-diearbalkoxyethyl) disulphide to decarboxylating hydrolysis by treating the same with a dilute strong acid, particularly dilute hydro chloric acid, under reflux at the boiling point of the mixture; the starting disulphide may be employed in the formof the crude product obtained by the reaction of an alkali metal lower alkyl amino (or lower alkyl lower alkanoylamido, or lower alkyl phthalimido) malon-ate with a bisahalomethyl disulphide in an anhydrous organic diluent, particularly ethanol, benzene, tolene or xylene, the diluent having been removed. Particular compounds the scope of the invention are: Bis B-amino-p, 3-dioarbethoxyethyl) disulphide.

substantially in the proportion of two molecular equivalents of the compound ofFormulalI per one molecular equivalent flof'the compound of Formula III. The re- 7 action medium may be a hydrocarbon such as benzene V C HrCOm CHr- SS C H2 -NHCOCH:

0111.00 0001B; (1v together with the disulphide of Formula V:

CgH OOC v COOCaH; onto oNH'-( J-c 'H=-s-s-oH,-$N1Icoom H0O 00H v) and the di-aza lactone compound of Formula C5HO0G 000023:

N- -CHr-S-S-CH2- --N UHF-C V C-CH:

0-c=0 o=o-0 V (VI) The calculated analysis of these compounds is as follows: Formula IV.C=45.80%; H=6.16%; N =5.34%; s=12.22%. Formula v.-c=41.02%; H =5.16%; N=5.98%; S==13.69%. Formula VI.C- =44.43%; H=4. 66%; -O=29.60%; N= 6.48%; s =14.83%. Y

or toluene or may be other organic liquids as hereinafter set forth. V

The product obtained in a crude form may contain partial hydrolysis products. Thus, using sodium ethyl acetylamido m alonate and bis-chloromethyl disulphide as the reactants there may be obtained the desired product of Formula IVzj.

ozHtoo'o comm.

The desired compound of Formula IV can be isolated Bis-(,B-formamido-fl,fi-dicarbethoxyethyl)disulphide.

Bis- B-acetarmdo-B,,B-dicarbethoxyethyl) disulphide; Bisfi-phthalimido-B,B-dicarb ethoxyethyl) disulphide. Bis-(fi-benzamido-,8,;8-dicarbethoxyethyl)disulphide.

According to a further 'feature of the invention the aforesaid compounds of general Formula I are produced by condensing, in an anhydrous organic medium a compound of the Formula 11:

where R R and R have the significance indicated above compound to produce cystine the by-products are also efiective it is generally unnecessary to purify the product for commerical use. 7

While the aforesaid process may be carried out, as

indicated above using benzene or toluene as the anhydrous organic medium, it is found that the condensation proceeds more rapidly and completely if the reactionis efiected in a medium of absolute ethanol.

The following examples will serve to illustrate the invention but are not to be regarded as limiting it in' any way: all the meltingpoints are measuredwith-a Thiele tube.

W -EXAMPLEr-T intermediizies 'A. Pure bis-chloromethyl disulphide (ClCH -S--SCH Cl) prepared and purified for example according to the data.

xylene, but the method is slow and not verypracticah' The following method of preparationis therefore pre-' ferred:, 1* f? cc. of anhydrous 2.82 g; or sodium are dissolved in so ethanol (distilled over magnesium according'to the technique indicated by Vogel, '3A Text Bookof Practical Organic Chemistryfi pp. 165-166) in a flash equipped with'fa; 'stirrerj'mec'hanism; 26.65 g. of anhydrous ethyl) acetamido malonateidissolved in 300 cc. of anhydrous .xylene, dibutyl ether, ethyl 'befizeneare their added gradually; qrhe flask is then r equipped with, a reflux condenser in, addition to the stirrer,

. 'mech'anism, the said condenserfbeingfitted atjflits end lacalciumfchloride tube. After foriZholirs: at boiling point, a yellowish-white.precipitatelbecomes. apparent. Distillation is then carried' out until there no longer any alcohol present in' tlie. distillate. For purpose, itis necessary to distil about200 cc4of sme r,

Process i V The distillation residue from B is'made up to 300' cc.

' withanhydrous be'nzene'and 10 g. of'the;purc bis ch1oromethyl disulphideare. added alluatpnces The-mixture is refluxedforlO hours. After cooling,tlie ben'zeneanrl'v thei'eaction products form a yellowish-white gel The benzene is driven off bydistillatio'n at ordinary pressure on an oil 'bath and then, under reduced pressure (20' mm), 36 g;.of,a white product are obtained. This iswashd indistilled water until free from chlorine ions 6 washing operation),

The product is then Worked up into 'a paste twice in boiling alcohol, this paste being dried after cooling and being dissolvedin 600 cc. of boiling ethanol (96% by volume) after cooling to f C. it is centrifuged and dried in vacuo over sulphuric acid; 17 g'. of a product are recovered, this productmelting at 178-179" C.

After being crystallised twice in ethanol, the melting point becomes constant at 181-184 C.; the yield is Analysisshows: a

Calculated (for compound of. Formula IV): N= .34%. Found: N =5,7O%. V

Calculated (for compound of Formula IV): S=12.22%. Found: S='l2.49-l2.81%.

5 g. of this product are washed with 40 cc. of 8% ammonia and'then with 40 cc. of, 10% aqueous hydro chloric acid, then washed in water and dissolved and recrystallised in 100 cc. of ethyl alcohol at 96; the melting: point remains at 181-184.

Analysis shows: e

Calculated: C==45.80%; I H=6.15%; N=5.34%;' S=12.22%*. Foundz, C=.41.26-41.18%; =5.52

5.55%; N=5.69-5.59%; S=13.75l3.61%. The product is dissolved and recrystallised. once again anol; it i's'insoluble at boiling point in cyclohexane, di isopropyl ether and diethyl ether.

As indicated above, compounds of different; Formulae: 1V, V and VI can resultQfromjhissynthesis. Others more or less hydrolysed --intern1ediate products may exist in m or proportions. r

Deacetylatedcompounds are no Accordingly it-is clearfr omthe analytical'figuresithat i the compound'obtained is fbis '(fl-acetamido-fl-B-dicarbl ethoxy ethyDdisulphide, 'contaminatediby partially hy drolysediprorlucts; such; as fthose of Formulas Vjand lndustrially ittis'oflittle interest to endeavourto isolate "the bis-(fl-acetamido-B-p=dicarbethoxy ethyl-)disul-'-- phide in the pure. state, because the'more or less hydrolysed compounds which accompany it themselves also" 4 lead to cystine 'th'e result not depending on the degree of purity of the disulphide.

Instead of operating in benzene, it is also possibleftoi r operated]; toluene; the reactionthen proceeds slightly more quickly. r V

EXAMPLE H Bis-(fi-acetgzmido-B-B-dicarboethoxy ethyl )disulphide (a) BEPArtATI N; 1N xrL NE 47.8 g. of sodium ethyl acetamidomalonate; are placed in 300 cc. of anhydrous xylene. The mixture is refluxed with stirring at 129-130 C. 16.3 g. of bis-chloromethyl disulphide are slowly introduced. The mixture is kept at boiling point for 4-hours. After cooling, the sodium chloride precipitate is isolated and washed three time? with boilingxylene and the solvent is driven off by vacuum distillation.

'The product isdi s'solved' and recrystallised in. a mixture ofc'ycloh'exane and xylene (:50). "About 30 grams of pure product are obtained, the melting point thereof being 125-125.5 C.-' I

The compound is soluble in'cold acetone and insoluble in water; it is sparingly soluble in ether and methanol, sparingly soluble'incold ethanol and very' soluble in hot ethanol, as well as in benzene.

Analysis-Calculated: N% =5.34;' 8% =12.22.

in anhydrous toluene and'then in 75 cc. of a mixture consisting, of equal par-ts of ethyl acetate, acetic acid and.

butanol- After beingpurified 'five times, the following data are found for the crystallisedfraction (melting point 183185.):

' 5 fCalculated: N= 5.34%;-S=12.22%. 1 Found: N=5.50- 5.45%} S-t',13.4313:27%. e

Found: N=5.s1

' thc same operational. units and closely similar analytical results were obtained.

:The recovered product is always insoluble in water,

insoluble in dilute hydrochloric and ammonia solutions,

insoluble-in concentrated ammonia but soluble in coni 1 ccntratedhydrochloric acid and concentrated acetic acid.

It is also soluble at boiling point in benzene, toluene,-

identical, they are .comf (b) PREPARATION 1m VANHYDROUS ALCOHOL 4.6 g. of sodium are dissolved in cc. of anhydrous 7 alcohol in a flask identical to thatpreviously referred to; After dissolution, 43.6 g. of ethyl acetamido malonatei are added while stirring mechanically. After being Iincontact for half an hour, 163g. of

' sulphide are added all at once. 7

The turejs refluxed with crystals are' obtained which melt at .125.5 C. The yield is 50 toy55%- of pureiproduct.

Analysis-Calculated: C%'=45.80; H%'=6.l0; N%

EXAMPLE In 'Bis-(fl-formamido-flfi dicafbethoxy ethyDdisulPhide (a) PREPARATION V IN XYLENE 45 g. of ethyl formamido malonate are placed with 350 cc. of anhydrous xylene ina 500 cc. flask equipped with mechanical stirrer device, a reflux condenser, a funnel and a thermometer. The mixture is brought to 50 to 60 C C. and 16.3 g. ofbis-chloromethyl disulphide are while stirring.

acetate, ethanol and meth- 1 V present 1 since the 5 product obtainedfdo'es.:riot':;produce1any 'colouririg ofi bis-chloromethyldi:

stirring'for 30 minutes.- I, After cooling, the sodiunr chlorideis eliminated'by'" 7' filtration and then. thefiltrate concentrated in vacu'o. The residue is dissolved and'recry'stallised in a boiling" mixture of cyclohex-ane and xylene (50:50). colourless I The mixture is then maintained under reflux for 2 hours. After cooling, the precipitate is separated on a fi'itted glass funnel and rinsed three times with boiling xylene. The filtrate is concentrated to a small volume,

the resulting precipitate is filtered oflf and then recrystal (b) PREPARATION IN ANHYDROUS ALCOHOL 200 cc. of absolute ethanol are placed with 4.6 g. of sodium in a flask equipped with the same devices as previously referred to. When the alcoholic solution is at a temperature of 40 0. there are added 40.6 g. of ethyl formamido malonate dissolved in 100 cc. of ethanol.

The mixture is stirred for half an hour. After this time, when the temperature is 30 C., 16.3 g. of bischloromethyl disulphide are introduced slowly and the mixture is heated under reflux for one hour.

- After cooling, the mixture is filtered in order to eliminate the sodium chloride which has formed; the alcohol is .removed by vacuum distillation and the residue is dissolved and recrystallised in a 50:50 mixture of isopropyl ether and benzene.

The yield of pure product is 75 to 80% and the melting point thereof is 107 C.

EXAMPLE IV Bis-(B-phthalimido-fi, fl-dicarbethoxy ethy1)disulphide (a) PREPARATIONIN XYLENE 4 66 of sodium ethyl phthalimido malonate are placed with 500 cc. of xylene and 16.3 g. of bis-chloromethyl disulphide in a 1 litre flask equipped with a mechanical stirrer device, a reflux condenser and a thermometer.

The mixture is brought to a condition of gentle reflux for 14 hours, on an oil bath adjusted to 55 C. After this time, the cooled mixture is filtered on a fritted glass funnel in such manner as to eliminate the sodium chloride.. This is washed three times with boiling xylene and then the filtrate and the combined washing waters are ,concentrated in vacuo to a small volume.

'The separated product is dissolved and recrystallised twice in boiling methanol. About grams of the desired product are obtained, its melting point being 113.5- IMOC' A considerable part of the ethyl phthalimido malonate which has not reacted and also of the bis-chloromethyl disulphide are recovered.

The product is insoluble in water, fairly soluble in hot cyclohexane and insoluble in cold cyclohexane, very soluble in hot methanol and insoluble in cold methanol, soluble in hot bntyl ether and insoluble in cold butyl ether, soluble in hot isopropyl ether and insoluble in cold isopropyl ether, soluble in hot dioxane and insoluble in cold dioxane, and very sparingly soluble in hot carbon tetrachloride.

Analysis.-Calculated: C%=54.85; H%=4.57; N% =4.00; S%=9.14. Found: C%=55.0054.90; H% =4.294.37; N%=4.00-4.16; S%=9.429.25.

S g. of a black resinous product is isolated in the crystallisation liquors.

(b) PREPARATION IN ANHYDROUS ALCOH OL 200 cc. of anhydrous alcohol and 4.6 g. of sodium are placed in a flask identical with that referred to above. When the temperature reaches 30 C., 64 g. of ethyl I phthalimido malonate diss'olved-in200 cc. of'ethanol are nated by extracting three times with diethyl ether.

added. After stirring for half an hour (time for forma .tion of the sodium salt), 16.3 gof bis-chloromethyl disulphide dissolved in '100 .ccof e thanol are. added. The introduction is completed in half an hour.

After this time, the mixture is kept for half an hour at ordinary temperature while stirring-and then the mixture is heated under reflux for 2% hours. After cooling, the solutionis filtered and the alcohol driven off under vacuum. The product is dissolved and recrystallised in methanol. There are obtained 4 6 g. of partially hydrolysed product, melting at 118.5-119" C. the 'remainder being in a syrupy condition.

Analysis.-Calculated: C%=54.85; H%=4.57; N% =4.00; 8% =9.14. Found: C%=54.57-54.36; H% =5.74-5.50; N%=3.57-3.60; S%=7.86-7.99.

Operating in accordance with the method of Example IVb but'replacing'the ethyl phthalimido malonateiby ethylbenzamidomalonate, a product is obtained which after 'being dissolved and recrystallised in isopropyl ether, has a melting point of 89 to 89.5? C.; the yield 4.32; 8% =9.88. Found: C%=55.35-55.15; H% =5.40-5.47; N% =4.25-4.32; S%'= 9.84-9.85.

' The product is insoluble in water, fairly soluble in cold methanol, sparingly soluble in cold ethanol and very soluble in hot ethanol, insoluble in petroleum ether, sparingly soluble in ethyl ether, very sparingly soluble in cold isopropyl ether but very soluble in hot isopropyl ether and soluble in cold benzene. i

EXAMPLE VI Preparation of bis- (p-aminofifi-dicarbethoxy,

'ethyDdisulphide' 200 cc. of anhydrous ethanol and 4.6 g. of sodium are placed in a flask similar to that of Example III. The solution is cooled to the region of 5 C. by an ice bath. There are then added 35 g. of ethyl amino malonate dissolved in cc.of anhydrous ethanol, while stirring and under a current of nitrogen.

After 20 minutes, a yellowish precipitate has been formed. 16.3 g. of bis-chloromethyl disulphide diluted in 100 cc. of anhydrous ethanol are then'added in half an hour. This operation-is carried out under nitrogen and while stirring.

After the introduction, the mixture is left at ordinary temperature for half an hour. It is then heated for 10 minutes at 40 C. It is necessary not to exceed this temperature so as to avoid causing liberation of hydrogen sulphide.

During the reaction, the heterogeneous mixture changes from yellow to a milky white colour. After cooling, the sodium chloride precipitate is removed by centrifuging and the solution is concentrated in vacuo at 30 C. or below. The ethanol is completely eliminated under nitrogen. I The oil obtained (yield 407 is dissolved in 33%% aqueous hydrochloric acid and the impurities are elimi- The hydrochloric acid solution is then neutralised by 33 /a% aqueous ammonia and the precipitated oil is taken up in diethyl ether. The ethereal solution is dried over sodium sulphate and the diethyl ether is completely driven off under vacuum.

This oily product cannot be obtained in crystalline form and cannot be distilled. In order to prove the identity of this product, it was treated with acetic anhydride; the acetamide derivative previously .descn'bed was obtained.

In the preceding examples, the alcohol which esterit are identical groups selected class consistingof I amino, formamido, acetamidofjbenzamido and ,phthalhol. 1

;We claim:; J 1.. 1 A compound.

tithe general formula: 5 anew wherein R, is a lower alkyl group. and the groups imido'group's'. i

r r '5; Bis-(d-phtlialimido 3 dicarbethoirye'thyndisulphide.

6.Bis-(B- benzami do 3.18. dicarbethoxyethyndisulphide. e i

7. A process. for theof a compound ofthe fies the carboxylic:groupscan zbe other ethyl alcoa where V are identical groups; selected from the class consisting of amino, formamido, acetamido, benzamido and phthalimido groups which comprises condensing in an anhydrous organic medium selected from the group consisting R QOC.

of benzene, toluene, xylene and ethanol, substantially 2 molecular equivalents of acompound of the formula:

iedefiriedg fahoir e, Xis km atom of where Y'is .ahalogen atom. I

8. A process fdr the production of a V the'general formula: 4

wherein R is a lo wer alkyl group and the groups are identical groups selected from the, classconsisfing of amino, formamido, ,acetamidd; benzamido .and phthal imido groups which comprises condensing in an anhy-:' drous ethanol medium substantially 2.xnoleeular equivais defined as ahove, X is an atom of an alkali metal, with one molecular equivalent of a compound of the formula:

V Y-CH SS---CH -Y where Y is a halogen atom.

References Cited in the file of this patent UNITED STATES PATENTS 2,393,327 Langkammerer Jan. 2-2, 1946 2,430,455 Crooks Nov. 11, 19471 2,466,232 Harris Apr. 5, 19491 2,4 s,1ssi Snyder et 1. Aug. 9,1949" OTHER REFERENCES 1 r swan; Nature, May 11, 1951p. 965.

,] lli 'me ak I one" molecular; equivalent of a compqund ofthe formula: 

1. A COMPOUND OF THE GENERAL FORMULA:
 5. BIS-(B-PHTHALIMIDO-B.B-DICARBETHOXYETHYL) DISULPHIDE. 